Coupling of two arenes with selenium dioxide to give a selenobiaryl ether

ABSTRACT

The present invention relates to a method for coupling two arenes with selenium dioxide to give a selenobiaryl ether. The method of the present invention includes: adding a first arene to the reaction mixture, adding a second arene to the reaction mixture, adding selenium dioxide to the reaction mixture, adding an acid having a pKa in the range from 0 to 5 to the reaction mixture, and adjusting the reaction temperature of the reaction mixture such that the first arene and the second arene are converted to a selenobiaryl ether. The present invention also relates to novel selenobiaryl ethers.

The invention relates to a method for coupling two arenes with seleniumdioxide to give a selenobiaryl ether, and also novel selenobiarylethers.

Selenobiaryl ethers are a highly interesting and promising class ofcompounds. These compounds are currently being incorporated intoparticular complexes, particularly those containing manganese, but havegreat potential for further uses.

The term “arenes” is used as a generic term in this application, andtherefore also encompasses substituted arenes, but not phenols.

T. K. Paine describes a synthesis of2,2′-selenobis(4,6-di-tert-butylphenol) using selenium dioxide. Thepreparation of 2,2′-selenobis(4,6-di-tert-butylphenol) is effected herein an acidic medium with addition of concentrated hydrochloric acid. Theproduct is obtained with a yield of 25% (T. K. Paine et al., “Manganesecomplexes of mixed O, X, O-donor ligands (X═S or Se): synthesis,characterization and catalytic reactivity”, Dalton Trans., 2003, 15,3136-3144).

It is particularly disadvantageous here that the yields are low andtherefore in need of improvement.

It is further problematic that hydrochloric acid is used since this ischlorine-containing. Chlorine-containing species lead to corrosion insteel reactors such that, in industrial scale syntheses, particularmeasures have to be taken which are frequently linked to majorinvestments (particular reactor materials for example). It is thereforedesirable to improve the process.

H. M. Lin describes a synthesis route for selenobiaryl ethers, which iseffected over several stages. First of all, bromine has to be added ontothe appropriate phenol, in order then to react the product withmagnesium to give a Grignard reagent. The Grignard reagent can thenreact with the added selenium before the actual coupling to give thebiaryl ether:

(H. M. Lin et al., “A novel and efficient synthesis of selenides”,ARKIVOC, 2012, viii, 146-156)

The product was obtained in a good yield, but this synthesis route isvery complex, which makes it unattractive for industrial scale use. Inthis case, a multitude of synthesis steps are needed, the procedure forwhich is not uncritical in some cases, especially considering scale-upand using standards which are customary in industry. Moreover, thissynthesis route gives rise to large amounts of waste products andsolvents which have to be disposed of in a costly and inconvenientmanner, one reason for which is the use of bromine.

It was an object of the invention to provide a method which does nothave the disadvantages described in connection with the prior art. Inparticular, a method by which selenobiaryl ethers can be prepared ingood yield should be provided. The process should also be usable on theindustrial scale, and therefore have a minimum number of individualsteps and intermediates.

This object is achieved by a method according to claim 1.

Method for preparing selenobiaryl ethers comprising the method steps of:

-   a) adding a first arene to the reaction mixture,-   b) adding a second arene to the reaction mixture,-   c) adding selenium dioxide to the reaction mixture,-   d) adding an acid having a pKa in the range from 0 to 5 to the    reaction mixture,-   e) adjusting the reaction temperature of the reaction mixture such    that the first arene and the second arene are converted to a    selenobiaryl ether.

Steps a) to d) can be conducted here in any sequence. Accordingly, areaction mixture is already present in the reaction vessel during theaddition or maybe not as in the case of the first addition.

The method is not restricted to the components described above. Furtherconstituents, for example solvents, may likewise be present in thereaction mixture.

If the acid has more than one pKa, the pKa₁ should be considered. In thecase of the invention, this has to be within the range from 0 to 5. Thedefinition of pKa is sufficiently well known to those skilled in the artand can be found in the appropriate technical literature.

An advantage over the methods described in the prior art is that it isnot necessary in this case to work with exclusion of moisture or oxygen.This constitutes a distinct advantage over other synthesis routes. Thismethod stands out advantageously from the existing multistage synthesisroutes.

Via the pKa, the reaction can be steered in the direction ofselenobiaryl ethers such that the resulting by-products are reduced. Asa result of predominant formation of the desired main product andreduction in the formation of higher molecular weight overoxidationproducts, the workup is distinctly simplified.

Unconverted reactants and solvents used can be recovered by distillationand used for further reactions. Thus, the method according to theinvention fulfils the requirements for an economic industrial scaleprocess.

Moreover, selenium dioxide is used in the method according to theinvention. Selenium dioxide is a waste product from metal purificationand ore refining. Thus, in the method claimed here, a waste product fromother processes is reused with addition of value. This is an importanttopic especially against the background of the sustainability ofprocesses.

In one variant of the method, the first arene in method step a) is acompound of the general formula I:

wherein R¹, R², R³, R⁴, R⁵ are each independently selected from:

-   —H, —(C₁-C₁₂)-alkyl, —O—(C₁-C₁₂)-alkyl, —(C₆-C₂₀)-aryl,    —O—(C₆-C₂₀)-aryl, -halogen (such as Cl, F, Br, I),    —OC═O—(C₁-C₁₂)-alkyl,-   two adjacent radicals may additionally be joined to one another to    form a condensed system,-   where the alkyl and aryl groups mentioned may be substituted,-   and at least one of the R¹, R², R³, R⁴, R⁵ radicals is —H.

(C₁-C₁₂)-Alkyl and O—(C₁-C₁₂)-alkyl may each be unsubstituted orsubstituted by one or more identical or different radicals selectedfrom:

-   (C₃-C₁₂)-cycloalkyl, (C₃-C₁₂)-heterocycloalkyl, (C₆-C₂₀)-aryl,    fluorine, chlorine, cyano, formyl, acyl or alkoxycarbonyl.

(C₆-C₂₀)-Aryl and O—(C₆-C₂₀)-aryl may each be unsubstituted orsubstituted by one or more identical or different radicals selectedfrom:

-   —H, —(C₁-C₁₂)-alkyl, —O—(C₁-C₁₂)-alkyl, —O—(C₆-C₂₀)-aryl,    -(C₆-C₂₀)-aryl, -halogen (such as Cl, F, Br, I),    —COO—(C₁-C₁₂)-alkyl, —CONH—(C₁-C₁₂)-alkyl,    —(C₆-C₂₀)-aryl-CON[(C₁-C₁₂)-alkyl]₂, —CO—(C₁-C₁₂)-alkyl,    —CO—(C₆-C₂₀)-aryl, —COOH, —OH, —SO₃H, —SO₃Na, —NO₂, —CN, —NH₂,    —N[(C₁-C₁₂)-alkyl]₂.

In the context of the invention, the expression (C₁-C₁₂)-alkylencompasses straight-chain and branched alkyl groups. Preferably, thesegroups are unsubstituted straight-chain or branched (C₁-C₈)-alkyl groupsand most preferably (C₁-C₆)-alkyl groups. Examples of (C₁-C₁₂)-alkylgroups are especially methyl, ethyl, propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 2-methylbutyl,3-methylbutyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl,2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 2-hexyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethylbutyl, 1-ethyl-2-methylpropyl, n-heptyl, 2-heptyl, 3-heptyl,2-ethylpentyl, 1-propylbutyl, n-octyl, 2-ethylhexyl, 2-propylheptyl,nonyl, decyl.

The elucidations relating to the expression “—(C₁-C₁₂)-alkyl” also applyto the alkyl groups in —O—(C₁-C₁₂)-alkyl, i.e. in —(C₁-C₁₂)-alkoxy.Preferably, these groups are unsubstituted straight-chain or branched—(C₁-C₆)-alkoxy groups.

Substituted (C₁-C₁₂)-alkyl groups and substituted (C₁-C₁₂)-alkoxy groupsmay have one or more substituents, depending on their chain length. Thesubstituents are preferably each independently selected from:

-   —(C₃-C₁₂)-cycloalkyl, —(C₃-C₁₂)-heterocycloalkyl, —(C₆-C₂₀)-aryl,    fluorine, chlorine, cyano, formyl, acyl or alkoxycarbonyl.

In one variant of the method, R¹, R², R³, R⁴, R⁵ are each independentlyselected from:

-   —H, —(C₁-C₁₂)-alkyl, —O—(C₁-C₁₂)-alkyl, —(C₆-C₂₀)-aryl,    —O—(C₆-C₂₀)-aryl,-   where the alkyl and aryl groups mentioned may be substituted,-   and at least one of the R¹, R², R³, R⁴, R⁵ radicals is —H.

In one variant of the method, R¹, R², R³, R⁴, R⁵ are each independentlyselected from:

-   —H, —(C₁-C₁₂)-alkyl, —O—(C₁-C₁₂)-alkyl.-   where the alkyl and aryl groups mentioned may be substituted,-   and at least one of the R¹, R², R³, R⁴, R⁵ radicals is —H.

In one variant of the method, R¹, R², R³, R⁴, R⁵ are each independentlyselected from:

-   —H, -CH₃, —O—CH₃,-   and at least one of the R¹, R², R³, R⁴, R⁵ radicals is —H.

In one variant of the method, the second arene in method step b) is acompound of the general formula II:

wherein R⁶, R⁷, R⁸, R⁹, R¹⁰ are each independently selected from:

-   —H, —(C₁-C₁₂)-alkyl, —(C₆-C₂₀)-aryl, —O—(C₆-C₂₀)-aryl, -halogen    (such as Cl, F, Br, I), —OC═O—(C₁-C₁₂)-alkyl,-   two adjacent radicals may additionally be joined to one another to    form a condensed system,-   where the alkyl and aryl groups mentioned may be substituted,-   and at least one of the R⁶, R⁷, R⁸, R⁹, R¹⁰ radicals is —H.

In one variant of the method, R⁶, R⁷, R⁸, R⁹, R¹⁰ are each independentlyselected from:

-   —H, —(C₁-C₁₂)-alkyl, —O—(C₁-C₁₂)-alkyl, —(C₆-C₂₀)-aryl, —O—(C₆    ⁻C₂₀)-aryl,-   where the alkyl and aryl groups mentioned may be substituted,-   and at least one of the R⁶, R⁷, R⁸, R⁹, R¹⁰ radicals is —H.

In one variant of the method, R⁶, R⁷, R⁸, R⁹, R¹⁰ are each independentlyselected from:

-   —H, —(C₁-C₁₂)-alkyl, —O—(C₁-C₁₂)-alkyl,-   where the alkyl and aryl groups mentioned may be substituted,-   and at least one of the R⁶, R⁷, R⁸, R⁹, R¹⁰ radicals is —H.

In one variant of the method, R⁶, R⁷, R⁸, R⁹, R¹⁰ are each independentlyselected from:

-   —H, —CH₃, —O—CH₃,-   and at least one of the R⁶, R⁷, R⁸, R⁹, R¹⁰ radicals is —H.

In one variant of the method, the first arene corresponds to the secondarene.

This variant is thus a homo-coupling of two identical arenes which arejoined via the selenium.

In one variant of the method, the selenium dioxide is added in methodstep c) in a molar ratio based on the sum total of the first and secondarenes within a range from 0.25 to 1.5.

Preference is given here to the range from 0.25 to 0.9, and particularpreference to the range from 0.4 to 0.7.

In one variant of the method, the acid is acetic acid.

In one variant of the method, the acid in method step d) is used assolvent.

In one variant of the method, the reaction mixture is adjusted in methodstep e) to a temperature in the range from 20° C. to 100° C.

Preference is given here to the range from 50° C. to 100° C., andparticular preference to the range from 80° C. to 90° C.

As well as the method, novel selenobiaryl ethers are also claimed.

Compound of the formula 1 or 2:

The invention is illustrated in detail hereinafter by working examples.

ANALYSIS

NMR Spectroscopy

The NMR spectroscopy studies were conducted on multi-nucleus resonancespectrometers of the AC 300 or AV II 400 type from Bruker, AnalytischeMesstechnik, Karlsruhe. The solvent used was CDCl₃. The ¹H and ¹³Cspectra were calibrated according to the residual content ofundeuterated solvent using the NMR Solvent Data Chart from CambridgeIsotopes Laboratories, USA. Some of the ¹H and ¹³C signals were assignedwith the aid of H,H-COSY, H,H-NOESY, H,C-HSQC and H,C-HMBC spectra. Thechemical shifts are reported as δ values in ppm. For the multiplicitiesof the NMR signals, the following abbreviations were used: s (singlet),bs (broad singlet), d (doublet), t (triplet), q (quartet), m(multiplet), dd (doublet of doublets), dt (doublet of triplets), tq(triplet of quartets). All coupling constants J were reported in hertz(Hz) together with the number of bonds covered. The numbering given inthe assignment of signals corresponds to the numbering shown in theformula schemes, which need not correspond to IUPAC nomenclature.

Bis(6-methyl-2,3,4-trimethoxyphenyl)selenium

In a 25 mL round-bottom flask, 0.27 g of selenium dioxide (2.4 mmol) wasadded to 0.80 g of 3,4,5-trimethoxytoluene (4.3 mmol) dissolved in 6 mLof acetic acid and the mixture heated to 85° C. in a hot oil bath. After12 days, the reaction mixture was filtered, the filtrate diluted withdichloromethane and washed with saturated sodium chloride solution. Theorganic phase was dried over magnesium sulphate and the solventdistilled off under reduced pressure. The crude product was purified bycolumn chromatography. The column length was 24 cm with a diameter of 3cm. Cyclohexane/ethyl acetate was used as eluent in a ratio of 9:1.

Yield: 0.399 g (0.9 mmol; 41%)

GC: R (hard method, HP-5)=16.250 min

TLC: R_(f) (CH:EE, 2:1)=0.4 ¹H-NMR: (400 MHz, CDCl3) δ[ppm]=2.37 (s,6H), 3.59 (s, 6H), 3.78 (s, 6H), 3.82 (s, 6H), 6.54 (s, 2H).

¹³C-NMR: (100 MHz, CDCl3) δ[ppm]=23.52 56.00, 60.60, 60.86, 109.17,118.21, 137.07, 140.44, 153.06, 154.19.

HRMS (ESI, pos. mode):m/z for [M+Na+]: calculated: 465.0792 found:465.0780

Bis(4,5-dimethoxy-2-methylphenyl)selenium

In a 25 mL round-bottom flask, 1.00 g of 3,4-dimethoxytoluene (6.5 mmol)was dissolved in 9 mL of acetic acid, 0.40 g of selenium dioxide (3.6mmol) was added and the mixture heated to 85° C. in a hot oil bath.After 12 days, the reaction mixture was filtered, the filtrate dilutedwith dichloromethane and washed with saturated sodium chloride solution.The organic phase was dried over magnesium sulphate and the solventdistilled off under reduced pressure. The crude product was purified bycolumn chromatography. In this case, an automated column system fromBÜCHI-Labortechnik GmbH, Essen was used. The column length was 16 cm andthe diameter 6 cm. The eluent used was cyclohexane/ethyl acetate,operating with an ethyl acetate gradient of: 0% (over 5 min), 1-5% (over5 min), 5-10% (over 8 min), 10-20% (8 min), 20-40% (10 min), 40-100% (10min). The pumping rate was 100 mL/min.

Yield: 0.637 g (1.6 mmol), 51%

GC: R (hard method, HP-5)=15.968 min

¹H-NMR: (400 MHz, CDCl3) δ[ppm]=2.34 (s, 6H), 3.70 (s, 6H), 3.86 (s,6H), 6.76 (s, 2H), 6.77 (s, 2H)

¹³C-NMR: (100 MHz, CDCl3) δ [ppm]=21.96, 56.07, 56.16, 113.47, 116.51,121.55, 132.50, 147.54, 148.70.

HRMS (ESI, pos. mode):m/z for [M+Na+]: calculated: 405.0581 found:405.0484

Both compounds 1 and 2 could each be synthesized in very good yields.Therefore, the stated problem is solved by the inventive method.

The invention claimed is:
 1. A method for preparing selenobiaryl etherscomprising: I) forming a reaction mixture by: a) adding a first arene tothe reaction mixture, b) adding a second arene to the reaction mixture,c) adding selenium dioxide to the reaction mixture, d) adding an acidhaving a pKa in the range from 0 to 5 to the reaction mixture, II)adjusting the reaction temperature of the reaction mixture to atemperature in the range from 20° C. to 100° C. such that the firstarene and the second arene are converted to the selenobiaryl ether,wherein the second arene does not include phenols, and wherein thewherein the first arene in method step a) is a compound of the generalformula I:

wherein R¹, R², R³, R⁴, R⁵ are each independently selected from: —H,—(C₁-C₁₂)-alkyl, —O—(C₁-C₁₂)-alkyl, —(C₆-C₂₀)-aryl, —O—(C₆-C₂₀)-aryl,-halogen, —OC═O—(C₁-C₁₂)-alkyl, two adjacent radicals may additionallybe joined to one another to form a condensed system, where the alkyl andaryl groups mentioned may be substituted, and at least one of the R¹,R², R³, R⁴, R⁵ radicals is —H.
 2. The method according to claim 1,wherein R¹, R², R³, R⁴, R⁵ are each independently selected from: —H,—(C₁-C₁₂)-alkyl, —O—(C₁-C₁₂)-alkyl, —(C₆-C₂₀)-aryl, —O—(C₆-C₂₀)-aryl,where the alkyl and aryl groups mentioned may be substituted, and atleast one of the R¹, R², R³, R⁴, R⁵ radicals is —H.
 3. The methodaccording to claim 1, wherein R¹, R², R³, R⁴, R⁵, are each independentlyselected from: —H, —(C₁-C₁₂)-alkyl, —O—(C₁-C₁₂)-alkyl, where the alkylgroups mentioned may be substituted, and at least one of the R¹, R², R³,R⁴, R⁵ radicals is —H.
 4. The method according to claim 1, wherein thesecond arene in method step b) is a compound of the general formula II:

wherein R⁶, R⁷, R⁸, R⁹, R¹⁰ are each independently selected from: —H,—(C₁-C₁₂)-alkyl, —O—(C₁-C₁₂)-alkyl, —(C₆-C₂₀)-aryl, —O—(C₆-C₂₀)-aryl,-halogen, —OC═O—(C₁-C₁₂)-alkyl, two adjacent radicals may additionallybe joined to one another to form a condensed system, where the alkyl andaryl groups mentioned may be substituted, and at least one of the R⁶,R⁷, R⁸, R⁹, R¹⁰ radicals is —H.
 5. The method according to claim 4,wherein R⁶, R⁷, R⁸, R⁹, R¹⁰ are each independently selected from: —H,—(C₁-C₁₂)-alkyl, —O—(C₁-C₁₂)-alkyl, —(C₆-C₂₀)-aryl, —O—(C₆-C₂₀)-aryl,where the alkyl and aryl groups mentioned may be substituted, and atleast one of the R⁶, R⁷, R⁸, R⁹, R¹⁰ radicals is —H.
 6. The methodaccording to claim 4, wherein R⁶, R⁷, R⁸, R⁹, R¹⁰ are each independentlyselected from: —H, —(C₁-C₁₂)-alkyl, —O—(C₁-C₁₂)-alkyl, where the alkyland aryl groups mentioned may be substituted, and at least one of theR⁶, R⁷, R⁸, R⁹, R¹⁰ radicals is —H.
 7. The method according to claim 4,wherein the first arene corresponds to the second arene.
 8. The methodaccording to claim 1, wherein the selenium dioxide is added in methodstep c) in a molar ratio based on the sum total of the first and secondarenes within a range from 0.25 to 1.5.
 9. The method according to claim1, wherein the acid is acetic acid.
 10. A compound of the formula 1 or2:


11. The method according to claim 1, wherein the added acid in step d)is present in amounts that forms a solution of dissolved first andsecond arenes and selenium dioxide.